Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Slitrk5 deficiency impairs corticostriatal circuitry and leads to obsessive-compulsive–like behaviors in mice

Abstract

Obsessive-compulsive disorder (OCD) is a common psychiatric disorder defined by the presence of obsessive thoughts and repetitive compulsive actions, and it often encompasses anxiety and depressive symptoms1,2. Recently, the corticostriatal circuitry has been implicated in the pathogenesis of OCD3,4. However, the etiology, pathophysiology and molecular basis of OCD remain unknown. Several studies indicate that the pathogenesis of OCD has a genetic component5,6,7,8. Here we demonstrate that loss of a neuron-specific transmembrane protein, SLIT and NTRK-like protein-5 (Slitrk5), leads to OCD-like behaviors in mice, which manifests as excessive self-grooming and increased anxiety-like behaviors, and is alleviated by the selective serotonin reuptake inhibitor fluoxetine. Slitrk5−/− mice show selective overactivation of the orbitofrontal cortex, abnormalities in striatal anatomy and cell morphology and alterations in glutamate receptor composition, which contribute to deficient corticostriatal neurotransmission. Thus, our studies identify Slitrk5 as an essential molecule at corticostriatal synapses and provide a new mouse model of OCD-like behaviors.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Targeted inactivation of Slitrk5 in mice and its expression pattern in the mouse brain.
Figure 2: Facial lesions, OCD-like behavior and its alleviation with fluoxetine treatment in Slitrk5-knockout mice.
Figure 3: Metabolic changes in the cortex and anatomical defects in the striatum of Slitrk5−/− mice.
Figure 4: Deficiency in corticostriatal transmission in Slitrk5−/− mice is mediated by changes in glutamate receptor composition.

References

  1. Miguel, E.C. et al. Obsessive-compulsive disorder phenotypes: implications for genetic studies. Mol. Psychiatry 10, 258–275 (2005).

    Article  CAS  Google Scholar 

  2. Karno, M., Golding, J.M., Sorenson, S.B. & Burnam, M.A. The epidemiology of obsessive-compulsive disorder in five US communities. Arch. Gen. Psychiatry 45, 1094–1099 (1988).

    Article  CAS  Google Scholar 

  3. Graybiel, A.M. & Rauch, S.L. Toward a neurobiology of obsessive-compulsive disorder. Neuron 28, 343–347 (2000).

    Article  CAS  Google Scholar 

  4. Menzies, L. et al. Integrating evidence from neuroimaging and neuropsychological studies of obsessive-compulsive disorder: the orbitofronto-striatal model revisited. Neurosci. Biobehav. Rev. 32, 525–549 (2008).

    Article  Google Scholar 

  5. Clifford, C.A., Murray, R.M. & Fulker, D.W. Genetic and environmental influences on obsessional traits and symptoms. Psychol. Med. 14, 791–800 (1984).

    Article  CAS  Google Scholar 

  6. Rasmussen, S.A. & Tsuang, M.T. The epidemiology of obsessive compulsive disorder. J. Clin. Psychiatry 45, 450–457 (1984).

    CAS  PubMed  Google Scholar 

  7. Pauls, D.L., Alsobrook, J.P. II, Goodman, W., Rasmussen, S. & Leckman, J.F. A family study of obsessive-compulsive disorder. Am. J. Psychiatry 152, 76–84 (1995).

    Article  CAS  Google Scholar 

  8. Nestadt, G. et al. A family study of obsessive-compulsive disorder. Arch. Gen. Psychiatry 57, 358–363 (2000).

    Article  CAS  Google Scholar 

  9. Hollander, E., Kim, S., Khanna, S. & Pallanti, S. Obsessive-compulsive disorder and obsessive-compulsive spectrum disorders: diagnostic and dimensional issues. CNS Spectr. 12, 5–13 (2007).

    Article  Google Scholar 

  10. Abelson, J.F. et al. Sequence variants in SLITRK1 are associated with Tourette′s syndrome. Science 310, 317–320 (2005).

    Article  CAS  Google Scholar 

  11. Aruga, J. & Mikoshiba, K. Identification and characterization of Slitrk, a novel neuronal transmembrane protein family controlling neurite outgrowth. Mol. Cell. Neurosci. 24, 117–129 (2003).

    Article  CAS  Google Scholar 

  12. Aruga, J., Yokota, N. & Mikoshiba, K. Human SLITRK family genes: genomic organization and expression profiling in normal brain and brain tumor tissue. Gene 315, 87–94 (2003).

    Article  CAS  Google Scholar 

  13. Katayama, K. et al. Slitrk1-deficient mice display elevated anxiety-like behavior and noradrenergic abnormalities. Mol. Psychiatry 15, 177–184 (2010).

    Article  CAS  Google Scholar 

  14. Shmelkov, S.V., Visser, J.W. & Belyavsky, A.V. Two-dimensional gene expression fingerprinting. Anal. Biochem. 290, 26–35 (2001).

    Article  CAS  Google Scholar 

  15. Milde, T. et al. A novel family of slitrk genes is expressed on hematopoietic stem cells and leukemias. Leukemia 21, 824–827 (2007).

    Article  CAS  Google Scholar 

  16. Valenzuela, D.M. et al. High-throughput engineering of the mouse genome coupled with high-resolution expression analysis. Nat. Biotechnol. 21, 652–659 (2003).

    Article  CAS  Google Scholar 

  17. Welch, J.M. et al. Cortico-striatal synaptic defects and OCD-like behaviours in Sapap3-mutant mice. Nature 448, 894–900 (2007).

    Article  CAS  Google Scholar 

  18. McClung, C.A. et al. DeltaFosB: a molecular switch for long-term adaptation in the brain. Brain Res. Mol. Brain Res. 132, 146–154 (2004).

    Article  CAS  Google Scholar 

  19. Saxena, S., Bota, R.G. & Brody, A.L. Brain-behavior relationships in obsessive-compulsive disorder. Semin. Clin. Neuropsychiatry 6, 82–101 (2001).

    Article  CAS  Google Scholar 

  20. Whiteside, S.P., Port, J.D. & Abramowitz, J.S. A meta-analysis of functional neuroimaging in obsessive-compulsive disorder. Psychiatry Res. 132, 69–79 (2004).

    Article  Google Scholar 

  21. Saxena, S. & Rauch, S.L. Functional neuroimaging and the neuroanatomy of obsessive-compulsive disorder. Psychiatr. Clin. North Am. 23, 563–586 (2000).

    Article  CAS  Google Scholar 

  22. Aylward, E.H. et al. Normal caudate nucleus in obsessive-compulsive disorder assessed by quantitative neuroimaging. Arch. Gen. Psychiatry 53, 577–584 (1996).

    Article  CAS  Google Scholar 

  23. Robinson, D. et al. Reduced caudate nucleus volume in obsessive-compulsive disorder. Arch. Gen. Psychiatry 52, 393–398 (1995).

    Article  CAS  Google Scholar 

  24. Rosenberg, D.R. et al. Frontostriatal measurement in treatment-naive children with obsessive-compulsive disorder. Arch. Gen. Psychiatry 54, 824–830 (1997).

    Article  CAS  Google Scholar 

  25. Szeszko, P.R. et al. Brain structural abnormalities in psychotropic drug-naive pediatric patients with obsessive-compulsive disorder. Am. J. Psychiatry 161, 1049–1056 (2004).

    Article  Google Scholar 

  26. Surmeier, D.J., Ding, J., Day, M., Wang, Z. & Shen, W. D1 and D2 dopamine-receptor modulation of striatal glutamatergic signaling in striatal medium spiny neurons. Trends Neurosci. 30, 228–235 (2007).

    Article  CAS  Google Scholar 

  27. Rauch, S.L. et al. Functional magnetic resonance imaging study of regional brain activation during implicit sequence learning in obsessive-compulsive disorder. Biol. Psychiatry 61, 330–336 (2007).

    Article  Google Scholar 

  28. Wang, L., Simpson, H.B. & Dulawa, S.C. Assessing the validity of current mouse genetic models of obsessive-compulsive disorder. Behav. Pharmacol. 20, 119–133 (2009).

    Article  CAS  Google Scholar 

  29. Joel, D. Current animal models of obsessive compulsive disorder: a critical review. Prog. Neuropsychopharmacol. Biol. Psychiatry 30, 374–388 (2006).

    Article  Google Scholar 

  30. Rauch, S.L. Neuroimaging and neurocircuitry models pertaining to the neurosurgical treatment of psychiatric disorders. Neurosurg. Clin. N. Am. 14, 213–223 vii–viii (2003).

    Article  Google Scholar 

  31. Cattaneo, E. et al. Loss of normal huntingtin function: new developments in Huntington′s disease research. Trends Neurosci. 24, 182–188 (2001).

    Article  CAS  Google Scholar 

  32. Deng, H., Le, W.D., Xie, W.J. & Jankovic, J. Examination of the SLITRK1 gene in Caucasian patients with Tourette syndrome. Acta Neurol. Scand. 114, 400–402 (2006).

    Article  CAS  Google Scholar 

  33. Keen-Kim, D. et al. Overrepresentation of rare variants in a specific ethnic group may confuse interpretation of association analyses. Hum. Mol. Genet. 15, 3324–3328 (2006).

    Article  CAS  Google Scholar 

  34. Chen, Z.Y. et al. Genetic variant BDNF (Val66Met) polymorphism alters anxiety-related behavior. Science 314, 140–143 (2006).

    Article  CAS  Google Scholar 

  35. Picconi, B. et al. Loss of bidirectional striatal synaptic plasticity in l-DOPA–induced dyskinesia. Nat. Neurosci. 6, 501–506 (2003).

    Article  CAS  Google Scholar 

  36. Lovinger, D.M., Tyler, E.C. & Merritt, A. Short- and long-term synaptic depression in rat neostriatum. J. Neurophysiol. 70, 1937–1949 (1993).

    Article  CAS  Google Scholar 

  37. Alger, B.E. & Teyler, T.J. Long-term and short-term plasticity in the CA1, CA3 and dentate regions of the rat hippocampal slice. Brain Res. 110, 463–480 (1976).

    Article  CAS  Google Scholar 

  38. Pereira, D.B. & Chao, M.V. The tyrosine kinase Fyn determines the localization of TrkB receptors in lipid rafts. J. Neurosci. 27, 4859–4869 (2007).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank M. Flint Beal for providing expertise on behavioral experiments. We thank G. Thurston for critical comments and suggestions. PSD95-cherry was a kind gift from R.H. Edwards (University of California–San Francisco). We acknowledge support from US National Institutes of Health grants MH079513 (F.S.L.) and NS052819 (F.S.L.), HL66592 (S.R.), HL097797 (S.R.) and AI080309 (S.R.), Burroughs Wellcome Foundation (F.S.L.), International Mental Health Research Organization (F.S.L.), the Sackler Institute (K.G.B., F.S.L.), DeWitt-Wallace Fund of the New York Community Trust (F.S.L.), Pritzker Consortium (F.S.L.), National Alliance for Research on Schizophrenia and Depression (S.V.S.), Mildred-Scheel-Stiftung, Deutsche Krebshilfe (T.M.), Gulbenkian PhD Programe in Biomedicine (C.C.P.), Fundacao para Ciencia e Tecnologia (C.C.P.), Howard Hughes Medical Institute (S.R.), Ansary Stem Cell Institute (S.R.), Anbinder and Newmans Own Foundations (S.R.), Qatar National Priorities Research Program (S.R.), Empire State Stem Cell Board (S.R.) and the New York State Department of Health grant NYS C024180 (S.R.).

Author information

Authors and Affiliations

Authors

Contributions

S.V.S. conceived of and designed the study, performed experiments, analyzed data and wrote the manuscript; A.H., D.J, C.C.P. and K.G.B. designed and performed experiments, analyzed data and assisted in writing the manuscript; T.M., E.S., J.S.K., M.B. and I.D. performed experiments and analyzed data; A.J.M., D.M.V., N.W.G. and G.D.Y. designed and generated the Slitrk5−/− mice; I.N. designed, performed and analyzed electrophysiology experiments; F.S.L. and S.R. conceived of and designed the study and wrote the manuscript.

Corresponding authors

Correspondence to Francis S Lee or Shahin Rafii.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–9 and Supplementary Methods (PDF 854 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Shmelkov, S., Hormigo, A., Jing, D. et al. Slitrk5 deficiency impairs corticostriatal circuitry and leads to obsessive-compulsive–like behaviors in mice. Nat Med 16, 598–602 (2010). https://doi.org/10.1038/nm.2125

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm.2125

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing